Herpes zoster occurs with increasing frequency and severity. Article

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1 Annals of Internal Medicine Article Safety of Herpes Zoster Vaccine in the Shingles Prevention Study A Randomized Trial Michael S. Simberkoff, MD; Robert D. Arbeit, MD; Gary R. Johnson, MS; Michael N. Oxman, MD; Kathy D. Boardman, RPh; Heather M. Williams, RN; Myron J. Levin, MD; Kenneth E. Schmader, MD; Lawrence D. Gelb, MD; Susan Keay, MD, PhD; Kathleen Neuzil, MD; Richard N. Greenberg, MD; Marie R. Griffin, MD; Larry E. Davis, MD; Vicki A. Morrison, MD; and Paula W. Annunziato, MD, for the Shingles Prevention Study Group Background: The herpes zoster vaccine is effective in preventing herpes zoster and postherpetic neuralgia in immunocompetent older adults. However, its safety has not been described in depth. Objective: To describe local adverse effects and short- and longterm safety profiles of herpes zoster vaccine in immunocompetent older adults. Design: Randomized, placebo-controlled trial with enrollment from November 1998 to September 2001 and follow-up through April 2004 (mean, 3.4 years). A Veterans Affairs Coordinating Center generated the permutated block randomization scheme, which was stratified by site and age. Participants and follow-up study personnel were blinded to treatment assignments. (ClinicalTrials.gov registration number: NCT ) Setting: 22 U.S. academic centers. Participants: immunocompetent adults 60 years or older, including 6616 who participated in an adverse events substudy. Intervention: Single dose of herpes zoster vaccine or placebo. Measurements: Serious adverse events and rashes in all participants and inoculation-site events in substudy participants during the first 42 days after inoculation. Thereafter, vaccination-related serious adverse events and deaths were monitored in all participants, and hospitalizations were monitored in substudy participants. Results: After inoculation, 255 (1.4%) vaccine recipients and 254 (1.4%) placebo recipients reported serious adverse events. Local inoculation-site side effects were reported by 1604 (48%) vaccine recipients and 539 (16%) placebo recipients in the substudy. A total of 977 (56.6%) of the vaccine recipients reporting local side effects were aged 60 to 69 years, and 627 (39.2%) were older than 70 years. After inoculation, herpes zoster occurred in 7 vaccine recipients versus 24 placebo recipients. Long-term follow-up (mean, 3.39 years) showed that rates of hospitalization or death did not differ between vaccine and placebo recipients. Limitations: Participants in the substudy were not randomly selected. Confirmation of reported serious adverse events with medical record data was not always obtained. Conclusion: vaccine is well tolerated in older, immunocompetent adults. Primary Funding Source: Cooperative Studies Program, Department of Veterans Affairs, Office of Research and Development; grants from Merck to the Veterans Affairs Cooperative Studies Program; and the James R. and Jesse V. Scott Fund for Shingles Research. Ann Intern Med. 2010;152: For author affiliations, see end of text. occurs with increasing frequency and severity with increasing age (1, 2). It is often associated with pain and discomfort that may interfere with functional status and quality of life during the acute phase. pain and discomfort may persist for weeks, months, or even years. This debilitating complication, known as postherpetic neuralgia, results in significant decrements in quality of life and ability to perform activities of daily living (2 4). Antiviral therapy has limited effect on the frequency and severity of postherpetic neuralgia. Therefore, a safe and effective vaccine to prevent herpes zoster and postherpetic neuralgia in older adults at greatest risk is highly desirable. We and others (5, 6) have reported that live attenuated Oka/Merck herpes zoster vaccine (Merck & Co., Whitehouse Station, New Jersey) is immunogenic in populations who have had varicella-zoster virus (VZV) infection, including older adults, and in persons lacking VZV antibody (6). Veterans Affairs Cooperative Study 403 (SPS [Shingles Prevention Study]) (7, 8) showed that herpes zoster vaccine was effective in preventing herpes zoster and postherpetic neuralgia in persons 60 years or older. Health care providers and patients need detailed information about the safety and tolerability, as well as efficacy, of a new vaccine to make informed decisions about its use. Determining the safety profile of herpes zoster vaccine was a major study objective. We present a comprehensive analysis of our observations. METHODS Design Overview The methods have been published elsewhere (7). The study was a randomized, placebo-controlled trial of herpes See also: Print Editors Notes Editorial comment Related article Summary for Patients....I-20 Web-Only Appendix Tables Appendix Figures Conversion of graphics into slides 4 May 2010 Annals of Internal Medicine Volume 152 Number 9 545

2 Article Safety of Herpes Zoster Vaccine Context The herpes zoster vaccine helps prevent herpes zoster and postherpetic neuralgia in older adults, but is it safe? Contribution This secondary report from a very large trial showed that few vaccine and placebo recipients, and equal numbers in both groups, reported serious adverse events (1.4%). More vaccine recipients than placebo recipients (48% vs. 16%) reported inoculation-site side effects, such as redness and tenderness. Inoculation-site side effects were more common in persons aged 60 to 69 years than in persons older than 70 years. Implication vaccine causes minor local inoculation-site adverse effects but no more serious adverse events than does placebo. The Editors zoster vaccine designed to test the vaccine s safety and efficacy. All participants and follow-up study personnel, except for personnel administering the vaccine, were blinded to treatment throughout the study until data were reviewed for accuracy and the database was locked. The study was approved by the Human Rights Committee of the West Haven Department of Veterans Affairs Cooperative Studies Program Coordinating Center, West Haven, Connecticut, and by the institutional review board at each site. Setting and Participants The study was conducted at 22 academic medical centers in the United States between 1998 and We enrolled immunocompetent adults 60 years or older with a history of chickenpox or more than 30 years of residence in the continental United States and no history of herpes zoster. The mean follow-up was 3.4 years. Randomization and Intervention At each site, we stratified consenting eligible participants by age (60 to 69 years or 70 years) and randomly assigned them to receive investigational herpes zoster vaccine or placebo. The Coordinating Center generated a permutated block randomization. Allocation to herpes zoster vaccine and placebo was balanced in blocks of 6 vials and in both of the prespecified age strata for each of the 22 study sites. Single-dose vials of herpes zoster vaccine (median potency, plaque-forming units per dose) and placebo were maintained at 20 C. Vials were reconstituted, and participants were inoculated subcutaneously in the nondominant deltoid region within 30 minutes after the vial was removed from the freezer. Study personnel who reconstituted the vials and inoculated the participants had no subsequent contact with them and no subsequent role in data collection or analysis. Follow-up Procedures and Outcome Measures Participants and study personnel responsible for follow-up assessments were blinded to treatment assignment. Participants were followed monthly, either by participant-initiated reports to a toll-free automated telephone response system or by direct calls from study site personnel. In addition, all participants were questioned about the occurrence of rashes and serious adverse events during the 42 days after inoculation. Early in the enrollment phase, approximately 300 participants at each study site (6616 overall) were also enrolled in an adverse events substudy. Participation in the substudy was voluntary and not randomized. Participants were asked to complete a detailed vaccination report card designed to capture all adverse events that occurred during the first 42 days after inoculation. The vaccination report card prompted persons to record oral temperature for the first 21 days, erythema, swelling, pain and tenderness, and rash at the inoculation site; any other inoculation-site related signs or symptoms; rashes away from the inoculation site; exacerbations of preexisting diseases; new local or systemic illnesses; hospitalizations; and any other event the patient considered medically important. Serious adverse events, defined by concurrent U.S. Food and Drug Administration and International Committee on Harmonization guidelines (9), were monitored throughout the study by both active and passive surveillance. They were reported on study-specific Med- Watch forms. During the first 42 days after inoculation, all enrolled persons were followed actively for serious adverse events. After that, investigators were instructed to report all deaths as well as any serious adverse event considered to be possibly, probably, or definitely related to vaccination. In addition, persons in the substudy were questioned monthly regarding hospitalizations. All MedWatch forms were reviewed by the Cooperative Studies Program Research Pharmacist, the National Study Coordinator, the Study Chairman, SPS personnel at the Coordinating Center, and personnel at Merck (investigational new drug holder for the vaccine). We resolved any questions by querying the site that reported the serious adverse event. Each adverse event was recorded on a specific study form and, before the study was unblinded, was coded by the site by using a controlled vocabulary system (Coding Symbols from a Thesaurus of Reaction Terms [COSTART]) (10). Three investigators blindly reviewed all serious adverse events reported during the 42 days after inoculation and assigned each event to 1 of 6 pathophysiologic categories. Appendix Table 1 (available at defines these categories. Discrepancies in assignment were resolved by discussion among these investigators May 2010 Annals of Internal Medicine Volume 152 Number 9

3 Safety of Herpes Zoster Vaccine Article Statistical Analysis All data were stored and analyzed at the Coordinating Center. We performed analyses by using SAS statistical software (SAS Institute, Cary, North Carolina). We calculated the rates of adverse events during the first 42 days after inoculation by dividing the number of persons with the event by the number of persons with safety follow-up. We calculated risk differences between groups (vaccine placebo) and 95% CIs by using an asymptotic method for the difference between 2 proportions; for analyses of treatment differences, including both age cohorts, we weighted the proportions by the number of participants with safety follow-up in each age stratum at the 22 sites (11). We calculated rates of serious adverse events, hospitalization, or death occurring at any time during follow-up by dividing the number of persons with at least 1 event by the number of person-years of safety follow-up. Cumulative event rates were calculated by using product-limit estimates for timeto-event data and compared treatment groups and age strata by using a log-rank test stratified by site. We performed post hoc analyses of severity and duration in participants who had an adverse event. Duration of adverse events was compared between groups by using the Wilcoxon rank-sum test, and severity of adverse events was compared between groups by using the Cochran Mantel Haenszel chi-square test statistic stratified by age and site. We used the time to the first occurrence of a serious adverse event in each person for the time-to-event analyses. When assessing severity of inoculation site or systemic adverse events, we used the report of the most severe adverse event per person, rather than the first report. We did not prespecify within-age stratum comparisons of risk between treatments; however, we performed them in response to questions to the study group on the safety of the vaccine in more elderly persons. Role of the Funding Source The trial was funded by the Cooperative Studies Program of the Department of Veterans Affairs, Office of Research and Development, and by a grant to the Veterans Affairs Cooperative Studies Program from Merck. Merck was involved in review of all completed MedWatch forms but not in coding the adverse events, contacting the sites, performing the statistical analyses reported here, preparing the manuscript, or submitting the manuscript for publication. An executive committee that included 2 nonvoting members employed by Merck was primarily responsible for the conduct of the study. RESULTS A total of older adults participated in this study (Figure 1). During the first 42 days after vaccination, we obtained safety follow-up data from (97%) participants. A total of 6575 (99%) of the 6616 substudy participants completed the vaccination report card. More than 95% of the trial participants were followed to the end of the study and completed a closeout interview (mean safety follow-up, 3.39 years; range, 1 day to 5.40 years). In persons without closeout interviews, 1598 (4.1%) were known to have died, 132 (0.3%) withdrew, and 113 (0.3%) were lost to follow-up. The proportion of persons completing safety surveillance and the reasons for or rates of incomplete follow-up did not differ between groups. In all participants, the frequency and distribution of vesicular rashes occurring during the first 42 days after vaccination differed between vaccine and placebo recipients. A varicella-like rash, defined as 1 or more ungrouped vesicles, occurred at the inoculation site more frequently in vaccine recipients than placebo recipients (0.11% vs. 0.04%); however, rates of rashes occurring elsewhere were similar (0.10% vs. 0.07%). The varicellalike rashes occurring at the inoculation site typically consisted of small numbers of vesicles, did not spread, and were transient (mean duration, 5.4 days in vaccine recipients and 6.7 days in placebo recipients). Varicellalike rashes away from the inoculation site tended to last longer than inoculation-site rashes (mean duration, 17.6 days [range, 3 to 110 days] in vaccine recipients and 18.6 days [range, 1 to 92 days] in placebo recipients). Of the non herpes zoster rashes, 11 were evaluated by central polymerase chain reaction (PCR) assay, and 5 were evaluated by local virus culture. All results were negative for both wild-type and Oka vaccine strain VZV. One vaccine recipient had a disseminated varicella-like rash on day 18 that was assessed as probably related to the inoculation but was not suspected to be herpes zoster. During the 42 days after inoculation, herpes zoster like rashes (defined as multiple vesicles in a dermatomal distribution) occurred more often in placebo recipients than vaccine recipients. Of these, herpes zoster was confirmed in 24 placebo recipients and 7 vaccine recipients. Specimens were available from all but 1 case in each treatment group, and all 29 tested positive for wild-type VZV DNA by PCR assay. None tested positive for the Oka vaccine strain VZV. In substudy participants, the most common adverse events at the inoculation site were erythema, swelling, and pain and tenderness (Table 1). For both treatment groups, inoculation-site adverse events were more common in younger persons than in older persons (Table 1). Most events were mild or moderate in severity (Table 2). Erythema and swelling at the inoculation site were the only events in which the intensity was statistically significantly greater in vaccine recipients than in placebo recipients. However, fewer than 1% of vaccine recipients reported them as severe. Erythema, swelling, pain and tenderness, and warmth at the inoculation site persisted for longer in vaccine recipients than placebo recipients (Appendix Table 2, available at Erythema was the only local adverse event that persisted longer in younger vaccine 4 May 2010 Annals of Internal Medicine Volume 152 Number 9 547

4 Article Safety of Herpes Zoster Vaccine Figure 1. Safety monitoring in the Shingles Prevention Study. Total study population Participants enrolled (n = ) event substudy (n = 6616 [17.2%]) Aged y (n = [53.8%]) Aged 70 y (n = [46.2%]) vaccine (n = ) Placebo (n = ) vaccine (n = 8892) Placebo (n = 8907) 42-d safety follow-up (97.3%) Completed (97.4%) 278 (2.7%) No contact 274 (2.6%) 42-d safety follow-up 8571 (96.4%) Completed 8622 (96.8%) 321 (3.6%) No contact 285 (3.2%) Entire study follow-up (97.4%) Completed (97.4%) 218 (2.1%) Died 246 (2.4%) 23 (0.2%) Withdrew 29 (0.3%) 28 (0.3%) Lost 21 (0.2%) Entire study follow-up 8250 (92.8%) Completed 8284 (93.0%) 575 (6.5%) Died 549 (6.2%) 42 (0.5%) Withdrew 55 (0.6%) 25 (0.3%) Lost 19 (0.2%) event substudy* Enrolled in the adverse event substudy (n = 6616) Aged y (n = 3459 [53.8%]) Aged 70 y (n = 3157 [46.2%]) vaccine (n = 1732) Placebo (n = 1727) vaccine (n = 1613) Placebo (n = 1544) 42-d safety follow-up 42-d safety follow-up 1726 (99.7%) Completed 1709 (99.0%) 6 (0.3%) No contact 18 (1.0%) 1600 (99.2%) Completed 1540 (96.8%) 13 (0.8%) No contact 4 (0.3%) Entire study follow-up 1673 (96.6%) Completed 1663 (96.3%) 45 (2.6%) Died 48 (2.8%) 7 (0.4%) Withdrew 11 (0.3%) 7 (0.4%) Lost 5 (0.3%) Entire study follow-up 1493 (92.6%) Completed 1428 (92.5%) 99 (6.1%) Died 106 (2.8%) 12 (0.7%) Withdrew 7 (0.3%) 9 (0.6%) Lost 3 (0.3%) * Enrollment into the adverse event substudy was independent of blinded random assignment to receive vaccine or placebo. During the first year of the study, we completed a convenience sample of 300 participants per site, with a target of 50% in each age group May 2010 Annals of Internal Medicine Volume 152 Number 9

5 Safety of Herpes Zoster Vaccine Article recipients than older recipients (data not shown). Pruritus at the inoculation site occurred more frequently in vaccine recipients than placebo recipients in both age strata (Table 1) and persisted longer in vaccine recipients than in placebo recipients (Appendix Table 2). Inoculation-site events occurred sooner after vaccination in placebo recipients than vaccine recipients (mean, 1.7 vs. 2.3 days; P 0.001), whereas the time to the first systemic adverse event (mean, 15.9 vs days) and the duration of systemic adverse events (mean, 14.8 vs days) were similar in vaccine and placebo recipients (data not shown). During the first 42 days after inoculation, serious adverse events were reported in 1.4% of all participants in each group (Table 3). The point estimates for risk difference between treatment groups were 0.12% or less when analyzed overall, by prespecified age strata, or by COSTART body system (Table 3). Rates of serious adverse events increased with age at similar rates in vaccine recipients and placebo recipients. A time-to-event analysis by age group for the whole study population showed no statistically significant difference between vaccine recipients and placebo recipients (Figure 2). We performed a post hoc analysis for serious adverse events that occurred during the 42 days after inoculation in all participants 80 years or older (Table 3). Follow-up of serious adverse events was available for 96.6% (1220 of 1263) of vaccine recipients and 96.6% (1289 of 1335) of placebo recipients in this age group. The overall rate of serious adverse events did not statistically significantly differ by treatment group in participants 80 years or older (risk difference, 0.6 percentage points [95% CI, 0.5 percentage points to 1.7 percentage points]), and there were no statistically significant differences between groups for any body system (COSTART) or Physiologic Diagnostic Category classification (data not shown). In substudy participants, the overall rate of serious adverse events during the 42 days after inoculation was 1.6% (Table 4). As reported elsewhere (7), the rate of serious adverse events was higher in vaccine recipients than in pla- Table 1. Events at the Inoculation Site in Substudy Participants Variable Aged 60 to 69 Years Aged >70 Years Risk Difference Herpes Zoster Vaccine Group Number Risk, % Placebo Group Number Risk, % Risk Difference (95% CI), percentage points* Herpes Zoster Vaccine Group Number Risk, % Placebo Group Number Risk, % Risk Difference (95% CI), percentage points* Between Age Strata in Vaccine Recipients (95% CI), percentage points* Enrolled persons Persons with safety follow-up Persons without safety follow-up Persons with (34.6 to 40.6) (22.5 to 28.4) 16.4 (13.1 to 19.8) inoculationsite adverse event event prompted for on the VRC Erythema (31.2 to 36.5) (21.1 to 26.2) 11.1 (8.0 to 14.3) Swelling (24.7 to 29.6) (13.9 to 18.2) 12.2 (9.2 to 15.1) Pain/tenderness (30.2 to 35.7) (16.0 to 21.0) 17.1 (13.9 to 20.2) Rash (0.2 to 1.2) ( 0.4 to 0.7) 0.2 ( 0.5 to 0.8) Self-reported adverse event Pruritus (7.1 to 10.1) (2.5 to 4.8) 4.6 (2.9 to 6.4) Hematoma ( 1.3 to 0.4) (0.1 to 1.8) 0.5 ( 1.5 to 0.3) Mass (0.7 to 1.9) (0.1 to 1.0) 0.8 (0.2 to 1.6) Warmth (1.1 to 2.8) (0.3 to 1.6) 1.0 (0.2 to 2.0) Other adverse event ( 0.1 to 1.3) ( 0.1 to 1.1) 0.3 ( 0.4 to 1.1) VRC vaccination report card. * We calculated the risk difference by subtracting the estimated risk for the placebo group from the estimated risk for the herpes zoster vaccine group. We computed the CI for the risk difference and the P value for testing whether the risk difference is different from 0 on the basis of an asymptotic method for difference of 2 binomial proportions. We stratified all analyses by site. Risk differences and 95% CIs are provided for events prompted for on the VRC and for self-reported events with an incidence rate 1%. We calculated the risk as the percentage of persons with 1 adverse event in persons with follow-up in each age group. P P Reported in 0.1% of persons. 4 May 2010 Annals of Internal Medicine Volume 152 Number 9 549

6 Article Safety of Herpes Zoster Vaccine Table 2. Severity of Inoculation-Site Events in Substudy Participants Inoculation-Site Event Herpes Zoster Vaccine Group Event, n (%) Placebo Group P Value for Difference in Severity* Erythema 1188 (100) 227 (100) Mild 924 (77.8) 218 (96.0) Moderate 209 (17.6) 7 (3.1) Severe 55 (4.6) 2 (0.9) Swelling 871 (100) 147 (100) Mild 678 (77.8) 139 (94.6) Moderate 157 (18.0) 7 (4.8) Severe 36 (4.1) 1 (0.7) Pain 1147 (100) 278 (100) Mild 1053 (91.8) 266 (95.7) Moderate 91 (7.9) 12 (4.3) Severe 3 (0.3) 0 (0.0) Rash 20 (100) 6 (100) 0.54 Mild 17 (85.0) 4 (33.3) Moderate 3 (10.0) 2 (66.7) Pruritus 237 (100) 33 (100) 0.28 Mild 208 (87.8) 30 (90.9) Moderate 27 (11.4) 2 (6.1) Severe 2 (0.8) 1 (3.0) Hematoma 53 (100) 46 (100) 0.42 Mild 46 (86.8) 41 (89.1) Moderate 5 (9.4) 5 (10.9) Severe 2 (3.8) 0 (0.0) Mass 30 (100) 2 (100) 0.60 Mild 25 (83.3) 2 (100.0) Moderate 5 (16.7) 0 (0.0) Warmth 57 (100) 11 (100) 0.94 Mild 52 (91.2) 10 (90.9) Moderate 5 (8.8) 1 (9.1) * For differences in distribution of intensity of the event between treatment groups (Cochran Mantel Haenszel chi-square test statistic controlling for age group and site). For erythema, but not for any other individual inoculation-site event, there was a significant effect of age on intensity in recipients of herpes zoster vaccine (P 0.048; data not shown). cebo recipients (1.9% vs. 1.3%; P 0.038, analysis stratified by age and site). Although some serious adverse events occurred more often in vaccine recipients than in placebo recipients (for example, cardiovascular body system classification in 20 vs. 12 persons, respectively), none of the differences at or below the level of body system was statistically significant (7). Because of limitations in diagnostic classifications based on body system, we further analyzed all serious adverse events that occurred during the first 42 days after vaccination by using pathophysiologic criteria (Appendix Table 1). We subclassified serious adverse events related to vascular disease on the basis of whether they were consistent with acute vascular pathology (for example, myocardial infarction, strokes) or with functional disturbance associated with underlying vascular disease (for example, congestive heart failure). The overall rates of vascular events (that is, vascular [pathology] plus vascular [functional]) were nearly identical between vaccine recipients and placebo recipients in the total study population (99 [0.5%] vs. 101 [0.6%]) (Table 3). When each category of vascular pathophysiology was considered separately, there were small numerical differences between treatment groups that were neither statistically significant nor clinically meaningful (Table 3). We observed similar results when we analyzed serious adverse events in the substudy (Table 4). Over the course of the entire study, rates of death in the total SPS population (Appendix Figure 1, available at and rates of hospitalization in the substudy (Appendix Figure 2, available at were greater in the older age stratum than in the younger age stratum. However, rates for each treatment group, both overall and by age strata, were essentially identical and did not vary appreciably over the course of the study. Of note, the death rate in study participants was substantially lower than that reported by the U.S. National Health Statistics May 2010 Annals of Internal Medicine Volume 152 Number 9

7 Safety of Herpes Zoster Vaccine Article for the general U.S. population 60 years or older (12). When we stratified the study population into 5-year age groups to match the U.S. National Health Statistics data, the mortality rate in each age group was less than half (43% to 49%) of that reported for the general population. This is predictable given the enrollment procedures, which excluded persons expected to have limited life expectancy or comorbid conditions associated with high risk for herpes zoster complications (for example, known immunosuppression), to ensure the safety of study participants and adequate duration of follow-up. DISCUSSION As shown elsewhere by the SPS (7), 1 dose of herpes zoster vaccine reduced the burden of illness due to herpes zoster, as well as the incidence of postherpetic neuralgia and herpes zoster. Our report further demonstrates that herpes zoster vaccine had remarkably low rates of acute local reactions and, across the study population, had no detectable effect on the rates of serious adverse events during the 42 days after inoculation or on the rates of death during the entire mean 3.39 years of follow-up. An important safety consideration for any live attenuated virus vaccine is that the vaccine not cause the disease it is designed to prevent. We reviewed all rashes reported by study participants during the 42 days after inoculation. Vesicular rashes at the injection site were more common in vaccine recipients than in placebo recipients, but overall these events were infrequent and limited in extent and duration. Neither wild-type nor Oka vaccine strain VZV was shown in these injectionsite lesions, either by culture or PCR assay, and there were no documented episodes of disseminated vesicular disease caused by vaccine virus. Table 3. Rates of Serious Events Occurring From Day 0 to 42 After Inoculation in the Total Study Population Variable Herpes Zoster Vaccine Group* Placebo Group Risk Difference (95% CI), percentage points P Value Any Serious Events, n >1 Serious Events, n (%) Any Serious Events, n >1 Serious Events, n (%) Enrolled persons (1.37) (1.36) 0.01 ( 0.23 to 0.25) 0.93 Age 60 to 69 y (1.12) (1.00) 0.12 ( 0.17 to 0.40) y (1.66) (1.78) 0.12 ( 0.51 to 0.27) to 80 y (1.57) (1.80) 0.23 ( 0.65 to 0.19) y (2.24) (1.64) 0.60 ( 0.49 to 1.74) 0.28 Body system (COSTART) General body (0.23) (0.24) 0.01 ( 0.11 to 0.09) 0.84 Cardiovascular (0.43) (0.38) 0.05 ( 0.08 to 0.18) 0.45 Digestive (0.19) (0.23) 0.04 ( 0.14 to 0.05) 0.37 Endocrine 1 1 (0.01) 4 3 (0.02) 0.01 ( 0.05 to 0.02) 0.32 Hemic and lymphatic 5 5 (0.03) 2 2 (0.01) 0.02 ( 0.02 to 0.06) 0.25 Metabolic/nutritional 5 5 (0.03) 3 2 (0.01) 0.02 ( 0.02 to 0.06) 0.25 Musculoskeletal (0.08) (0.07) 0.00 ( 0.06 to 0.06) 0.99 Nervous system (0.17) (0.18) 0.01 ( 0.10 to 0.08) 0.82 Respiratory (0.15) (0.12) 0.03 ( 0.05 to 0.11) 0.48 Skin (0.14) (0.16) 0.02 ( 0.10 to 0.07) 0.70 Sight/sense 4 4 (0.02) 0 0 (0.00) 0.02 (0.00 to 0.06) Genitourinary (0.09) (0.09) 0.01 ( 0.07 to 0.06) 0.86 Diagnostic group Vascular (pathology) (0.32) (0.36) 0.04 ( 0.16 to 0.12) 0.55 Vascular (functional) (0.21) (0.18) 0.03 ( 0.06 to 0.12) 0.54 Cancer (0.26) (0.25) 0.02 ( 0.09 to 0.12) 0.76 Infection (0.15) (0.10) 0.05 ( 0.03 to 0.13) Accident (0.07) (0.06) 0.01 ( 0.05 to 0.07) 0.83 Allergic reaction 3 3 (0.02) 4 3 (0.02) 0.00 ( 0.04 to 0.04) 1.00 Autoimmune disorder 2 2 (0.01) 2 2 (0.01) 0.00 ( 0.03 to 0.03) 0.99 Other (0.33) (0.38) 0.05 ( 0.18 to 0.07) 0.39 COSTART Coding Symbols from a Thesaurus of Reaction Terms. * participants enrolled, participants with safety follow-up participants enrolled, participants with safety follow-up. At time of enrollment. Not a prespecified age stratum or a prespecified analysis. Appendix Table 1 (available at defines the diagnostic groups. 4 May 2010 Annals of Internal Medicine Volume 152 Number 9 551

8 Article Safety of Herpes Zoster Vaccine Cumulative SAE Rate, % Figure 2. Time to first SAE from day 0 to day 42 for the total study population Placebo, y vaccine, y Placebo, 70 y vaccine, 70 y Time to First SAE, d The cumulative rates of SAEs are shown for the time to the first SAE from days 0 to 42 after inoculation in all study participants. There is no significant treatment difference within age strata: For persons aged 60 to 69 years, log-rank P 0.41; for persons 70 years or older, log-rank P Overall treatment comparison: log-rank P Comparison of age strata 60 to 69 years versus 70 years or older: log-rank P SAE serious adverse event. The prespecified primary efficacy analysis excluded cases of herpes zoster that occurred during the first 30 days after vaccination. However, in the safety analysis of all vesicular rashes during the first 42 days after inoculation, herpes zoster occurred more frequently in placebo recipients than in vaccine recipients (24 vs. 7 confirmed cases, respectively), indicating not only that herpes zoster vaccine did not cause herpes zoster but that it protected against herpes zoster during this early period, as well as later. The early onset of vaccine-induced protection is consistent with immunologic studies (13) indicating that VZVseropositive, latently infected persons have an anamnestic response to herpes zoster vaccine. Inoculation-site reactions were the primary difference in the rate of adverse events in recipients of herpes zoster vaccine versus placebo in the immediate postinoculation period. These reactions were typically transient and rarely severe. Overall, the reactions were similar to those observed in recipients of other vaccines recommended for older adults (14). Inoculation-site reactions were statistically significantly more frequent and intense in younger vaccine recipients than in older recipients. We reported elsewhere (5) that the immune response to herpes zoster vaccine was more vigorous in younger participants than in older participants. These findings suggest that the local side effects of the herpes zoster vaccine may have been mediated by immune responses to the attenuated vaccine virus. Per protocol, during the 42 days after inoculation, there was active surveillance across the study for the occurrence of serious adverse events, and nearly all persons were explicitly questioned. There were no differences or suggestive trends in the frequency or distribution of serious adverse events between vaccine and placebo recipients in the total study population in any of the prespecified analyses, including by age strata, COSTART body system and subterms, and time-to-event analysis. The last is particularly compelling because vaccine-associated serious adverse events would be expected to show temporal clustering (15, 16). While our study was in progress, reports based on uncontrolled observations (17 20) suggested that smallpox vaccine was associated with acute cardiovascular adverse events, including ischemia. One proposed mechanism (17) was that inflammatory mediators (for example, -interferon and tumor necrosis factor) generated during the immune response to that live virus vaccine might have increased the risk for acute vascular pathology. Therefore, in addition to the prespecified safety analyses, we conducted 2 post hoc analyses to address concerns about any possible vaccine-associated increase in the risk for vascular events in older adults, who are the target population for herpes zoster vaccine. Rates of serious adverse events in the 42 days after inoculation did not statistically significantly differ in vaccine and placebo recipients 80 years or older, potentially the most vulnerable trial participants. In addition, while blinded to individual treatment assignments, we classified each adverse event on the basis of inferred pathophysiology, with particular emphasis on cardiovascular and cerebrovascular events. These analyses also found no statistically significant or clinically meaningful differences between recipients of herpes zoster vaccine and placebo. The substudy, which included approximately one sixth of the total study population, was designed to provide detailed information about relatively high-frequency, vaccination-related events (for example, inoculation-site events). Although participants were not selected at random, enrollment was well balanced by treatment in each age stratum. The proportion of persons with 1 or more serious adverse events was essentially the same in the substudy as in the total study population, indicating that ascertainment of the low-frequency but medically important events was similar in both populations. However, in contrast to the total study population, serious adverse events in the substudy were statistically more frequent in vaccine recipients than in placebo recipients (P 0.038). This difference was not reflected in the prespecified analyses by age strata or by using the COSTART classification method; specifically, there were no statistically significant differences for specific events or at the level of body system except for the sight/sense system, in which there were only 4 events. Our post hoc analysis, which was blinded and in which serious adverse events were classified by pathophysio May 2010 Annals of Internal Medicine Volume 152 Number 9

9 Safety of Herpes Zoster Vaccine Article Table 4. Rates of Serious Events Occurring From Day 0 to 42 After Inoculation in the Event Substudy Variable Herpes Zoster Vaccine Group* Placebo Group Risk Difference (95% CI), percentage points P Value Any Serious Events, n >1 Serious Events, n (%) Any Serious Events, n >1 Serious Events, n (%) Enrolled persons (1.93) (1.29) 0.64 (0.04 to 1.28) Body system (COSTART) General body (0.30) 7 7 (0.22) 0.08 ( 0.20 to 0.38) 0.50 Cardiovascular (0.61) (0.37) 0.24 ( 0.11 to 0.62) Digestive 8 7 (0.21) 12 9 (0.29) 0.07 ( 0.37 to 0.20) 0.55 Endocrine Hemic and lymphatic 2 2 (0.06) ( 0.06 to 0.24) Metabolic/nutritional 3 3 (0.09) 1 1 (0.03) 0.06 ( 0.10 to 0.26) 0.33 Musculoskeletal 5 5 (0.15) 1 1 (0.03) 0.12 ( 0.05 to 0.35) Nervous system (0.37) 6 6 (0.18) 0.19 ( 0.08 to 0.50) Respiratory 4 4 (0.12) 5 5 (0.16) 0.04 ( 0.28 to 0.18) 0.66 Skin 6 5 (0.15) 4 3 (0.09) 0.06 ( 0.15 to 0.30) 0.50 Sight/sense 2 2 (0.06) ( 0.06 to 0.24) Genitourinary 5 5 (0.15) 2 2 (0.07) 0.08 ( 0.12 to 0.31) 0.35 Diagnostic group Vascular (pathology) (0.52) 9 9 (0.27) 0.25 ( 0.06 to 0.61) Vascular (functional) (0.31) 9 8 (0.25) 0.05 ( 0.23 to 0.36) 0.67 Cancer 8 8 (0.24) 5 5 (0.15) 0.09 ( 0.16 to 0.36) 0.43 Infection 8 6 (0.18) 8 7 (0.22) 0.04 ( 0.31 to 0.22) 0.71 Accident 6 6 (0.18) 2 2 (0.06) 0.11 ( 0.08 to 0.36) Allergic reaction (0.03) 0.03 ( 0.19 to 0.08) 0.28 Autoimmune disorder Other (0.51) 13 9 (0.30) 0.21 ( 0.11 to 0.54) COSTART Coding Symbols from a Thesaurus of Reaction Terms. * 3345 participants enrolled, 3326 participants with safety follow-up participants enrolled, 3249 participants with safety follow-up. Appendix Table 1 (available at defines the diagnostic groups. logic category, also revealed no statistically significant differences in rates of these events in the recipients of herpes zoster vaccine versus placebo in the substudy. In addition, beyond 42 days after inoculation, the treatment groups did not differ in any analysis. On the basis of all available data and analyses, we conclude that the observed difference in rates of serious adverse events in the vaccine recipients and placebo recipients in the substudy, although statistically significant, represents a chance occurrence in a selected subgroup and does not reflect vaccine-related events. Our study has limitations. At enrollment, participants were ambulatory and noninstitutionalized and 95% were white. We excluded severely debilitated older adults and those with known immunosuppressive disease or treatment. The safety and efficacy of herpes zoster vaccine in such populations are uncertain. Participants in the substudy were not randomly selected. Serious adverse events not treated at study sites were assessed by participants reports and, although efforts were made in every case, these were not always confirmed by medical record review. In summary, our analyses showed that herpes zoster vaccine was well tolerated and safe in older immunocompetent adults. There was a modest increase in the rate of acute inoculation-site events in vaccine recipients, but no increased risk for herpes zoster itself and no pattern suggesting any serious adverse events were causally related to vaccination. Given the substantial protection that herpes zoster vaccine provides against the occurrence and morbidity of herpes zoster and, specifically, postherpetic neuralgia, we believe that this safety profile supports the recommendation for routine use of herpes zoster vaccine in immunocompetent older adults, who are at increased risk for herpes zoster and its complications (21). From Veterans Affairs New York Harbor Healthcare System and New York University School of Medicine, New York, New York; Tufts University School of Medicine, Boston, Massachusetts; Veterans Affairs Cooperative Studies Program Coordinating Center, West Haven, Connecticut; Veterans Affairs San Diego Healthcare System and University of California, San Diego, San Diego, California; New Mexico Veterans Affairs Health Care System, Albuquerque, New Mexico; National Cancer Institute, National Institutes of Health, Bethesda, Maryland; University of Colorado Denver, Aurora, Colorado; Geriatric Research Education and Clinical Center (GRECC), Durham Veterans Affairs Medical Center, Durham, North Carolina; St. Louis Veterans Affairs Medical Center, St. Louis, Missouri; Baltimore Veterans Affairs Medical Center and University of Maryland School of Medicine, Baltimore, Maryland; University of Washington School of Medicine, Seattle, Washington; 4 May 2010 Annals of Internal Medicine Volume 152 Number 9 553

10 Article Safety of Herpes Zoster Vaccine Lexington Veterans Affairs Medical Center, Lexington, Kentucky; GRECC, Veterans Affairs Tennessee Valley Healthcare System, and Vanderbilt University School of Medicine, Nashville, Tennessee; Minneapolis Veterans Affairs Medical Center and University of Minnesota School of Medicine, Minneapolis, Minnesota; and Merck, Whitehouse Station, New Jersey. Some of the data from this article were presented at the 48th Annual International Conference on Antimicrobial Agents and Chemotherapy/ Infectious Diseases Society of America 46th Annual Meeting, Washington, DC, October Disclaimer: This study was conducted by the Cooperative Studies Program of the Department of Veterans Affairs in collaboration with the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and Merck. Grant Support: By the Cooperative Studies Program of the Department of Veterans Affairs, Office of Research and Development; Merck; and the James R. and Jesse V. Scott Fund for Shingles Research. Potential Conflicts of Interest: Disclosures can be viewed at M Reproducible Research Statement: Study protocol: Not available, but additional methods information is available at and Statistical code and data set: Not available. Requests for Single Reprints: Michael S. Simberkoff, MD, Veterans Affairs New York Harbor Healthcare System, 423 East 23rd Street, New York, NY 10010; , Current author addresses and author contributions are available at References 1. Hope-Simpson RE. The nature of herpes zoster: a long-term study and a new hypothesis. Proc R Soc Med. 1965;58:9-20. [PMID: ] 2. Chidiac C, Bruxelle J, Daures JP, Hoang-Xuan T, Morel P, LeplègeA,etal. Characteristics of patients with herpes zoster on presentation to practitioners in France. Clin Infect Dis. 2001;33:62-9. [PMID: ] 3. Schmader KE, Sloane R, Pieper C, Coplan PM, Nikas A, Saddier P, et al. The impact of acute herpes zoster pain and discomfort on functional status and quality of life in older adults. Clin J Pain. 2007;23: [PMID: ] 4. van Seventer R, Sadosky A, Lucero M, Dukes E. A cross-sectional survey of health state impairment and treatment patterns in patients with postherpetic neuralgia. Age Ageing. 2006;35: [PMID: ] 5. Levin MJ, Oxman MN, Zhang JH, Johnson GR, Stanley H, Hayward AR, et al; Veterans Affairs Cooperative Studies Program Shingles Prevention Study Investigators. Varicella-zoster virus-specific immune responses in elderly recipients of a herpes zoster vaccine. J Infect Dis. 2008;197: [PMID: ] 6. Macaladad N, Marcano T, Guzman M, Moya J, Jurado F, Thompson M, et al. Safety and immunogenicity of a zoster vaccine in varicella-zoster virus seronegative and low-seropositive healthy adults. Vaccine. 2007;25: [PMID: ] 7. Oxman MN, Levin MJ, Johnson GR, Schmader KE, Straus SE, Gelb LD, et al; Shingles Prevention Study Group. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med. 2005;352: [PMID: ] 8. Oxman MN, Levin MJ; Shingles Prevention Study Group. Vaccination against herpes zoster and postherpetic neuralgia. J Infect Dis. 2008;197 Suppl 2:S [PMID: ] 9. ICH Clinical Safety Data Management Guidance: Definitions and Standards for Expedited Reporting. Accessed at /Guidances/UCM pdf on 9 March COSTART: Coding Symbols for Thesaurus of Reaction Terms. Fifth Edition. Rockville, MD: U.S. Food and Drug Administration. Report no. FDA/CDER-95/ Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med. 1985;4: [PMID: ] 12. Kung HC, Hoyert DL, Xu J, Murphy SL. Deaths: Final Data for National Vital Statistics Reports. Hyattsville, MD: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics, National Vital Statistics System; Accessed at http: //cdc.gov/nchs/data/nvsr/nvsr56/nvsr56_10.pdf on 9 March Arvin AM. Cell-mediated immunity to varicella-zoster virus. J Infect Dis. 1992;166 Suppl 1:S [PMID: ] 14. Centers for Disease Control and Prevention. Update: vaccine side effects, adverse reactions, contraindications, and precautions. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 1996;45:1-35. [PMID: ] 15. Murphy TV, Gargiullo PM, Massoudi MS, Nelson DB, Jumaan AO, Okoro CA, et al; Rotavirus Intussusception Investigation Team. Intussusception among infants given an oral rotavirus vaccine. N Engl J Med. 2001;344: [PMID: ] 16. Murphy BR, Morens DM, Simonsen L, Chanock RM, La Montagne JR, Kapikian AZ. Reappraisal of the association of intussusception with the licensed live rotavirus vaccine challenges initial conclusions. J Infect Dis. 2003;187: [PMID: ] 17. Centers for Disease Control and Prevention (CDC). Smallpox vaccine adverse events among civilians United States, March 4-10, MMWR Morb Mortal Wkly Rep. 2003;52: [PMID: ] 18. Cassimatis DC, Atwood JE, Engler RM, Linz PE, Grabenstein JD, Vernalis MN. Smallpox vaccination and myopericarditis: a clinical review. J Am Coll Cardiol. 2004;43: [PMID: ] 19. Swerdlow DL, Roper MH, Morgan J, Schieber RA, Sperling LS, Sniadack MM, et al; Smallpox Vaccine Cardiac Events Working Group. Ischemic cardiac events during the Department of Health and Human Services Smallpox Vaccination Program, Clin Infect Dis. 2008;46 Suppl 3:S [PMID: ] 20. Sniadack MM, Neff LJ, Swerdlow DL, Schieber RA, McCauley MM, Mootrey GT. Follow-up of cardiovascular adverse events after smallpox vaccination among civilians in the United States, Clin Infect Dis. 2008;46 Suppl 3:S [PMID: ] 21. Harpaz R, Ortega-Sanchez IR, Seward JF; Centers for Disease Control and Prevention. Prevention of Herpes Zoster: Recommendations of the Advisory Committee on Immunization Practices (ACIP). Accessed at /preview/mmwrhtml/rr5705a1.htm?s_cid rr5705a1_e on 9 March May 2010 Annals of Internal Medicine Volume 152 Number 9

11 Annals of Internal Medicine Current Author Addresses: Dr. Simberkoff: Veterans Affairs New York Harbor Healthcare System, 423 East 23rd Street, New York, NY Dr. Arbeit: Division of Infectious Diseases, Tufts Medical Center, 800 Washington Street, Boston, MA Mr. Johnson: Cooperative Studies Program Coordinating Center (151- A), Veterans Affairs Connecticut Healthcare System, 950 Campbell Avenue, West Haven, CT Dr. Oxman: Shingles Prevention Study (111F-1), Veterans Affairs Medical Center, 3350 La Jolla Village Drive, San Diego, CA Ms. Boardman: Veterans Affairs Cooperative Studies Program, Pharmacy Coordinating Center (151-I), Department of Veterans Affairs Medical Center, 2401 Center Avenue Southeast, Albuquerque, NM Ms. Williams: National Cancer Institute, Medical Oncology Branch, Building 10, Room 12N226, 10 Center Drive, Bethesda, MD Dr. Levin: University of Colorado, Pediatric Infectious Diseases, MS C227, Building 401, 1784 Racine Street, Room R09-108, PO Box 6508, Aurora, CO Dr. Schmader: Geriatric Research Education and Clinical Center (182), Veterans Affairs Medical Center, 508 Fulton Street, Durham, NC Dr. Gelb: 370 Lyonnais Drive, Creve Coeur, MO Dr. Keay: Veterans Affairs Medical Center, Room 3B-184, 10 North Green Street, Baltimore, MD Dr. Neuzil: PATH, 2201 Westlake Avenue, Suite 200, Seattle, WA Dr. Greenberg: University of Kentucky School of Medicine, Department of Medicine, Room MN-672, 800 Rose Street, Lexington, KY Dr. Griffin: Department of Preventive Medicine, Vanderbilt University Medical Center, st Avenue South, Village at Vanderbilt, Suite 2600, Nashville, TN Dr. Davis: Veterans Affairs Medical Center, Research Service, Building T12-A, 1501 San Pedro Southeast, Albuquerque, NM Dr. Morrison: Hematology/Oncology and Infectious Disease Section, Veterans Affairs Medical Center, One Veterans Drive (111-E), Minneapolis, MN Dr. Annunziato: Merck & Co., Inc., Mailstop Location UG3CD-28, PO Box 1000, North Wales, PA Author Contributions: Conception and design: R.D. Arbeit, G.R. Johnson, M.N. Oxman, M.J. Levin, K.E. Schmader, L.D. Gelb, L.E. Davis, V.A. Morrison. Analysis and interpretation of the data: M.S. Simberkoff, R.D. Arbeit, G.R. Johnson, M.N. Oxman, M.J. Levin, K.E. Schmader, L.D. Gelb, S. Keay, K. Neuzil, V.A. Morrison. Drafting of the article: M.S. Simberkoff, R.D. Arbeit, G.R. Johnson, M.N. Oxman, H.M. Williams, M.J. Levin, K.E. Schmader, L.D. Gelb, S. Keay, R.N. Greenberg, L.E. Davis, V.A. Morrison. Critical revision of the article for important intellectual content: M.S. Simberkoff, R.D. Arbeit, G.R. Johnson, M.N. Oxman, K.D. Boardman, M.J. Levin, K.E. Schmader, K. Neuzil, R.N. Greenberg, M.R. Griffin, V.A. Morrison, P.W. Annunziato. Final approval of the article: M.S. Simberkoff, R.D. Arbeit, G.R. Johnson, M.N. Oxman, K.D. Boardman, H.M. Williams, M.J. Levin, K.E. Schmader, L.D. Gelb, S. Keay, K. Neuzil, R.N. Greenberg, M.R. Griffin, L.E. Davis, V.A. Morrison, P.W. Annunziato. Provision of study materials or patients: M.S. Simberkoff, G.R. Johnson, M.N. Oxman, M.J. Levin, K.E. Schmader, L.D. Gelb, S. Keay, K. Neuzil, R.N. Greenberg, M.R. Griffin, L.E. Davis, V.A. Morrison. Statistical expertise: G.R. Johnson. Obtaining of funding: G.R. Johnson, M.N. Oxman, K.E. Schmader. Administrative, technical, or logistic support: R.D. Arbeit, G.R. Johnson, M.N. Oxman, K.D. Boardman, H.M. Williams, M.J. Levin, L.D. Gelb, L.E. Davis, P.W. Annunziato. Collection and assembly of data: M.S. Simberkoff, R.D. Arbeit, G.R. Johnson, M.N. Oxman, K.D. Boardman, H.M. Williams, M.J. Levin, K.E. Schmader, L.D. Gelb, S. Keay, K. Neuzil, M.R. Griffin, L.E. Davis, V.A. Morrison. Appendix Table 1. Physiologic Diagnostic Categories Used for Review of Serious Events Category Vascular (pathology) Vascular (functional) Autoimmune disorder Allergic reaction Infection Cancer Accident Other Description Cardiovascular events in which there was a priori or documented evidence of vascular abnormality not previously apparent. Included any cardiovascular events that were fatal, had documented tissue damage (for example, myocardial infarction, cerebrovascular accident, or transient ischemic attack), or resulted in vascular surgery (for example, stent or coronary artery bypass grafting). Cardiovascular events that had no clear evidence of short-term abnormality; could be purely functional events occurring in the absence of new or active vascular pathology (for example, arrhythmias, hypertension, syncope, congestive heart failure, or chest pain). Disorders observed were polymyalgia rheumatica, temporal arteritis, and Hashimoto thyroiditis. Acute allergic events, including angioedema and drug reactions. Acute infections (for example, pneumonia, cellulitis, or urinary tract infection). Newly diagnosed carcinomas, melanomas, lymphomas, leukemia. Restricted to falls, motor vehicle accidents, and injury. Two persons had falls after syncope; syncope was coded separately in 1 person and not in the other. All events not assigned to one of the previous categories, including musculoskeletal chest pain, gastrointestinal or endocrine disorders, mental status changes, behavioral changes, and seizures. W May 2010 Annals of Internal Medicine Volume 152 Number 9